Asymmetric grignard synthesis with cyclic 1,2 aminoalcohols

ABSTRACT

Processes for preparing a single enantiomer of an α,α-disubstituted-α-hydroxy acetic acid, especially cyclohexylphenylglycolic acid (CHPGA), is disclosed. The processes employ cyclic 1,2-aminoalcohols as chiral auxiliaries by forming diastereomeric esters of aminoalcohols or diastereomeric amides of oxazolidines. ##STR1## Intermediates useful in the process are also disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application, Ser. No.09/050,825, filed Mar. 30, 1998, the entire disclosure of which isincorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to chemical processes and to intermediatesin those processes.

BACKGROUND OF THE INVENTION

α,α-Disubstituted-α-hydroxy acetic acids are starting materials andintermediates for manufacturing compounds that have important biologicaland therapeutic activities. Such compounds include, for example,oxybutynin, oxyphencyclimine, oxyphenonium bromide, oxypyrroniumbromide, and oxysonium iodide, for which cyclohexylphenylglycolic acid(CHPGA) is of special interest.

Racemic CHPGA is generally prepared by one of two methods: (1) selectivehydrogenation of phenyl mandelic acid or of phenyl mandelate esters, asshown in Scheme 1; or (2) cyclohexyl magnesium halide addition tophenylglyoxylate as shown in Scheme 2. ##STR2## R is hydrogen or loweralkyl. ##STR3##

The synthesis of individual enantiomers of CHPGA has been approachedalong the lines of Scheme 2, by Grignard addition to a chiral auxiliaryester of glyoxylic acid to give a diastereomeric mixture of esters. Ingeneral, simple primary alkyl or phenyl Grignard (or alkyllithium)reagents were used for the addition, and the addition of inorganic salts(e.g. ZnCl₂) sometimes appeared to increase the diastereoselectivity ofthe products. As outlined in Scheme 3, the simple chiral ester whereinR* is the residue of a chiral alcohol, can be hydrolyzed to yield chiralCHPGA (R'=-H), or directly converted to chiral drugs or drug candidatesby trans-esterification (R'=acetate), for example by reaction with anamino alcohol side chain to prepare S-oxybutynin. ##STR4## While thesemethods are adequate for many purposes, the chemical yields are in somecases poor, and the stereoselectivity is not always high. The chiralauxiliary reagents that give good yields and higher stereoselectivityare often quite expensive. There remains therefore a need for a highlystereoselective synthesis of CHPGA and related compounds that provideshigh chemical yields at lower cost.

SUMMARY OF THE INVENTION

This need is satisfied, the limitations of the prior art overcome, andother benefits realized in accordance with the principles of the presentinvention, which in one aspect relates to a process for theenantioselective synthesis of a chiral α-hydroxycarboxylate. The processcomprises:

(a) reacting a prochiral α-ketocarboxylic acid with a single enantiomerof an N-substituted vicinal aminoalcohol of cyclopentane, cyclohexane,cycloheptane, indane, tetralin or benzosuberane to form an ester of theα-ketocarboxylic acid;

(b) reacting the ester with an excess of a Grignard reagent in anethereal solvent at 20° to -78° C. to provide a reaction mixturecontaining a diastereomer of an α-hydroxycarboxylate ester;

(c) separating a single diastereomer of the α-hydroxycarboxylate esterfrom the reaction mixture; and, optionally,

(d) hydrolyzing the α-hydroxycarboxylate ester to provide anα-hydroxycarboxylic acid or α-hydroxycarboxylate salt enriched in oneenantiomer.

A salt of zinc, cerium, titanium, iron or copper may be added to step(b). Separation of the single diastereomer of α-hydroxycarboxylate esterfrom the reaction mixture may be accomplished by fractionalcrystallization or chromatography. Hydrolysis may be carried out withaqueous alkali metal hydroxide or enzymatically. In one embodiment, theprochiral α-ketocarboxylic acid is reacted with a single enantiomer of avicinal aminoalcohol by forming an acid chloride and reacting the acidchloride with the aminoalcohol. In another embodiment, the prochiralα-ketocarboxylic acid is reacted with a single enantiomer of a vicinalaminoalcohol by activation with a carbodiimide. In preferredembodiments, the prochiral α-ketocarboxylic acid is eitherphenylglyoxylic acid or cyclohexylglyoxylic acid and the singleenantiomer of a vicinal aminoalcohol is a single enantiomer of2-tosylamino-1-cyclopentanol, 2-tosylamino-1-cyclohexanol,1-tosylamino-2-indanol, 2-tosylamino-2-phenyl-1-cyclohexanol or1-dimethylamino-2-indanol.

In another aspect, the invention relates to a process for theenantioselective synthesis of a chiral α-hydroxycarboxylate comprising:

(a) reacting an acid chloride of a prochiral α-ketocarboxylic acid witha single enantiomer of a vicinal aminoalcohol of cyclopentane,cyclohexane, cycloheptane, indane, tetralin or benzosuberane in thepresence of an enol ether of a lower alkylketone or a dialkoxyalkane andstrong organic acid or anhydrous Lewis acid catalyst to form a2,2-dialkyl-1-glyoxylyloxazolidine;

(b) reacting the 2,2-dialkyl-1-glyoxylyloxazolidine with an excess of aGrignard reagent in an ethereal solvent at 20° to -78° C. to provide areaction mixture containing a2,2-dialkyl-1-(β-hydroxy-α-oxomethyl)oxazolidine;

(c) separating a single diastereomer of2,2-dialkyl-1-(β-hydroxy-α-oxomethyl)oxazolidine from the reactionmixture; and

(d) hydrolyzing the 2,2-dialkyl-1-(β-hydroxy-α-oxomethyl)oxazolidine toprovide an α-hydroxycarboxylic acid or α-hydroxycarboxylate saltenriched in one enantiomer.

As before, a salt of zinc, cerium, titanium, iron or copper may be addedto step (b). The hydrolysis of the oxazolidine may be carried outsequentially with aqueous mineral acid, followed by alkali metalhydroxide in a high boiling solvent or an enzyme in an aqueous medium.In preferred embodiments, the prochiral α-ketocarboxylic acid is eitherphenylglyoxylic acid or cyclohexylglyoxylic acid; the single enantiomerof a vicinal aminoalcohol is 2-amino-1-cyclopentanol,2-amino-1-cyclohexanol or 1-amino-2-indanol; the enol ether is2-methoxypropene; the ammonium salt catalyst is pyridiniumtoluenesulfonate; and the Grignard reagent is a cycloalkylmagnesiumhalide or a phenylmagnesium halide.

In another aspect, the invention relates to compounds useful asintermediates in the foregoing processes. In the following disclosure,the variables are defined when introduced and retain that definitionthroughout. The compounds useful as intermediates in the foregoingprocesses include compounds of formula IVa ##STR5## wherein R¹ is chosenfrom the group of alkyl, cycloalkyl, and arylsulfonyl;

R² is alkyl or cycloalkyl, or, when R¹ is arylsulfonyl, R² mayadditionally be hydrogen;

or together R¹ and R² are alkylene, ##STR6## or ##STR7## R³ is one ormore substituents chosen independently from the group of hydrogen,alkyl, alkoxyl and halo;

n is 1,2,3 or 4; and

A is a cyclic residue chosen from the group of cyclopentane,cyclohexane, cycloheptane, indane, tetralin or benzosuberane.

They also include compounds of formula III ##STR8## wherein A has aconfiguration such that the compounds are either pure enantiomers orpredominantly one enantiomer. Preferred subgenera include those in whichR³ is hydrogen; those in which A is cyclopentane, cyclohexane, tetralin,or most preferably indane; those in which R¹ is methyl ortoluenesulfonyl and R² is hydrogen or methyl; and those in which R¹ istoluenesulfonyl and R² is hydrogen. Particularly preferred are compoundsof formulae ##STR9##

Other compounds useful as intermediates include compounds of formulaVIIIa, VIIa and VIIb: ##STR10## wherein R⁴ and R⁵ are lower alkyl or,taken together, R⁴ and R⁵ are a carbonyl function. Preferred compoundsare those in which R³ is hydrogen; in which A is cyclopentane,cyclohexane, tetralin, or most preferably, indane; and in which R⁴ andR⁵ are both methyl.

DETAILED DESCRIPTION

The graphic representations of racemic, ambiscalemic and scalernic orenantiomerically pure compounds used herein are taken from Maehr J.Chem. Ed. 62, 114-120 (1985): solid and broken wedges are used to denotethe absolute configuration of a chiral element; wavy lines indicatedisavowal of any stereochemical implication which the bond it representscould generate; solid and broken bold lines are geometric descriptorsindicating the relative configuration shown but denoting racemiccharacter; and wedge outlines and dotted or broken lines denoteenantiomerically pure compounds of indeterminate absolute configuration.Thus, for example, the formula X is intended to encompass both of theenantiomerically pure trans 1-amino-2-hydroxytetralins: ##STR11## Theterm "enantiomeric excess" is well known in the art and is defined for aresolution of ab→a+b as ##EQU1## The term "enantiomeric excess" isrelated to the older term "optical purity" in that both are measures ofthe same phenomenon. The value of ee will be a number from 0 to 100,zero being racemic and 100 being pure, single enantiomer. A compoundwhich in the past might have been called 98% optically pure is now moreprecisely described as 96% ee.; in other words, a 90% e.e. reflects thepresence of 95% of one enantiomer and 5% of the other in the material inquestion. The term "diastereomeric excess (d.e.) is similarly defined as##EQU2## in which p and q are diastereomers, and 90% de reflects 95% ofp and 5% of q. The diastereomeric excess is a measure of thediastereoselectivity of a reaction or process. "Alkyl", as used herein,refers to saturated hydrocarbon residues containing twenty or fewercarbons in straight or branched chains, as well as cyclic structures."Lower alkyl" is 6 or fewer carbons. "Alkoxy" refers to the sameresidues, containing, in addition, an oxygen atom at the point ofattachment. "Aryl" includes phenyl, substituted phenyl, naphthyl and thelike.

The processes of the invention are generically illustrated in Schemes 4and 5. Scheme 4 depicts the process when the amino functionality of theaminoalcohol is not reactive with an activated acid, either by virtue ofit being fully substituted or being rendered non-nucleophilic, e.g byformation of a sulfonamide. In this case, the hydroxyl of theaminoalcohol forms an ester with the carboxylic acid. Scheme 5 depictsthe process when the amine is a primary amine and is thus capable ofreacting with an activated carboxylic acid. In this case, the amineforms an amide with the carboxylic acid, and the hydroxyl, in thepresence of an enol ether or a gem dialkoxyalkane, forms a1,3-oxazolidine with the amine. ##STR12## In Scheme 4, a pure enantiomerof a cis aminoalcohol II is shown for ease of understanding, but a pureenantiomer of a trans aminoalcohol could also be used, and indeed manyare disclosed below. R⁶ is any residue that is unreactive towards aGrignard reagent, and R⁷ is any residue that can form a Grignardreagent. Commonly, R⁶ and R⁷ are alkyl or aryl or alkyl or arylsubstituted with one or more of alkoxy, alkyl or fluoroalkyl. In theexamples below, R⁶ and R⁷ are phenyl and cyclohexyl. The acid I is shownas a free acid, but it will be apparent to the artisan that the acidcould be in the form of an activated derivative, such as an acidchloride or anhydride.

The condensation of α-ketoacid I with cyclic 1,2-aminoalcohol II can beaccomplished by any of the numerous ways known in the art for formingesters. For example, the α-ketoacid may be reacted with thionyl chlorideor oxalyl chloride and the resulting the α-ketoacid chloride may then bereacted with the cyclic 1,2-aminoalcohol in the presence of a base toprovide the aminoester III. Condensing agents for reacting the alcoholII with the acid I include carbodiimides of various sorts, mixedanhydrides, EEDQ, HATU, and the like. It is also possible to pre-reactthe carboxylic acid with an appropriate leaving group, so as to form ananhydride or, in some cases even an activated ester. Grignard additionto the chiral ester provides the CHPGA ester. By selecting chiralauxiliary and carrying the reaction under certain conditions, theGrignard reagent approaches the ketone functional group preferentiallyfrom one face, and selective addition takes place to yield α-hydroxyacidesters in high diastereomeric excess (d.e.). Hydrolysis of the esterprovides the chiral (R or S) acid. Hydrolysis may be carriedconventionally with aqueous base or with any of the well known enzymesthat are commercially available, particularly the lipase class ofesterases.

Two preferred embodiments provide CHPGA via complementary routes. In thefirst embodiment, phenylglyoxylic acid is reacted with a singleenantiomer of a vicinal amino alcohol derivative of cyclopentane,cyclohexane, cycloheptane, indane, tetralin or benzosuberane to form anester of the phenylglyoxylic acid, the ester is reacted with an excessof cyclohexylmagnesium bromide in an ethereal solvent, optionally in thepresence of a zinc salt, at 20°to -78° C. to provide a reaction mixturecontaining an α-cyclohexylphenylglycolate ester; and a singlediastereomer of α-cyclohexylphenylglycolate ester is separated from thereaction mixture. In the second route, a cyclohexylglyoxylic acid isreacted with a single enantiomer of a vicinal aminoalcohol derivative ofcyclopentane, cyclohexane, cycloheptane, indane, tetralin orbenzosuberane to form an ester of the cyclohexylglyoxylic acid; theester is reacted with an excess of phenylmagnesium bromide in anethereal solvent at 20° to -78° C. to provide a reaction mixturecontaining an α-cyclohexylphenylglycolate ester; and a singlediastereomer of α-cyclohexylphenylglycolate ester is separated from thereaction mixture. In both cases the single diastereomer ofα-cyclohexylphenylglycolate ester is hydrolyzed to provideα-cyclohexylphenylglycolic acid or an α-cyclohexylphenylglycolate saltenriched in one enantiomer.

As is well known in the art, Grignard reactions are commonly carried outin so-called "ethereal solvents". By this is meant that the solventcontains at least one C--O--C bond. Typical ethereal solvents includediethyl ether, methyl t-butyl ether, tetrahydrofuran (THF), dioxane,glyme (dimethoxyethane) and the like.

The N-substituted chiral aminoalcohols used in the synthesis are readilyprepared from the corresponding aminoalcohol by tosylation oralkylation. Treatment of the chiral aminoalcohols with toluenesulfonylchloride in dichloromethane in the presence of triethylamine (3 eq) for3 h, provides N-tosylaminoalcohols in 70-90% yield. The startingaminoalcohols are commercially available or are prepared via Jacobsonoxidation, Sharpless dihydroxylation and Jacobson ring-openingtechnology, followed by Ritter Reaction. The benzosuberaneaminoalcohols, for example, are prepared in this fashion frombenzocycloheptene, respectively. Syntheses of individual enantiomers ofcyclic aminoalcohols are described in U.S. Pat. Nos. 5,516,943 and5,677,469, and in Senanayake et al. Tetrahedron Letters 36, 7615-7618(1995), the disclosures of which are incorporated herein by reference.The N-methylaminoindanol is prepared in two steps. Formylation of thecis-aminoindanol with formic acid gives the formyl amide in 85% yield.The amide is then reacted with borane in THF under reflux to give theN-methyl aminoindanol in 75% yield. N,N-Disubstituted aminoindanol isprepared by treatment of the cis-aminoindanol with formic acid andformaldehyde at 70° C. for 12 h. Some of the chiral auxiliaries preparedare shown in FIG. 2. Their antipodes can be similarly prepared in thefashion described above. ##STR13## Compounds in which R¹ and R² takentogether are phthaloyl or oxoisoindoline are prepared by treating theappropriate aminoalcohol with phthalic anhydride or methyl2-(bromomethyl) benzoate, respectively.

Reaction of these aminoalcohols with phenylglyoxylic acid in thepresence of DCC provides the corresponding esters. Alternatively,benzoylformic acid (or cyclohexylglyoxylic acid) is first treated with1.5 equivalents of thionyl chloride at 70° C. for 1-2 h (or oxalylchloride at 0° C. for 3 h) to give the acid chloride. The acid chlorideis then reacted with the aminoalcohols to give the esters in 70-90%yields.

Cyclohexylglyoxylic acid is prepared by Grignard addition of cyclohexylmagnesium chloride to diethyl oxalate in 80-87% yield. Hydrolysis of theester with NaOH yields the acid. The acid is converted to its chlorideby treating with oxalyl chloride in dichloromethane at 0-15° C., and thecrude acid chloride is reacted with tosylaminoindanol in dichloromethaneat 0° C. to provide the ester in 73% yield after silica gel flashchromatography.

A number of chiral esters of phenylglyoxylic acid were dissolved in THFand added to a solution of cyclohexylmagnesium chloride and ZnCl₂ (ratioca 1:1) at -78° C. (substrate: Grignard=1:3.5). After the addition, thereaction mixture was stirred for 30 min at that temperature and waswarmed to rt and stirred for 2-12 h. The diastereomeric ratios of theproducts ranged from 1:1 to 6.6:1. Purification by crystallization orflash column chromatography of the crude product yielded a singlediastereomer of the chiral CHPGA ester. When the order was reversed,i.e. phenyl Grignard was reacted with the cyclohexyl glyoxylate, and thereaction carried out in the absence of ZnCl₂, the d.e was very high.Results are shown in Table 1:

                  TABLE 1                                                         ______________________________________                                                                                 diaster-                                                                            omer                             R.sup.1 R.sup.2 A R.sup.6 R.sup.7 ratio                                     ______________________________________                                        tosyl H       cyclohexyl(1S,2S)                                                                          phenyl cyclohexyl                                                                           5.6:1                                  tosyl H indanyl(1R,2R) phenyl cyclohexyl 6.6:1                                tosyl H tetralinyl(1R,2S) phenyl cyclohexyl 6:1                               tosyl H 2-phenyl- phenyl cyclohexyl 6.6:1                                       cyclohexyl(1S,2R)                                                           tosyl methyl indanyl(1R,2S) phenyl cyclohexyl 4:1                             methyl methyl indanyl(1R,2S) phenyl cyclohexyl 5.2:1                          tosyl H indanyl(1R,2S) phenyl cyclohexyl 5:1                                  tosyl H indanyl(1S,2R) cyclohexyl phenyl >49:1                              ______________________________________                                    

When treated with sodium hydroxide in a water-methanol mixture, theester from the Grignard addition gives the chiral CHPGA withoutracemization in 76% yield at 70° C.; in addition, the chiral auxiliaryaminoalcohol (N-tosyl-aminoindanol) is recovered in 85% yield, asindicated in Scheme 4. The ability to recover the auxiliary in highyield is an advantageous feature of the process of the invention. Itgreatly reduces cost by allowing recycling of the auxiliary reagent.

A variant of scheme 4 in which the aminoalcohol carries a primary amineis shown in Scheme 5: ##STR14##

In the process shown in Scheme 5, an acid chloride of a prochiralα-ketocarboxylic acid I' is reacted with a single enantiomer of avicinal aminoalcohol II' of cyclopentane, cyclohexane, cycloheptane,indane, tetralin or benzosuberane in the presence of an enol ether of alower alkylketone VI and a strong organic acid or anhydrous Lewis acidcatalyst. Alternatively, the acid chloride may be reacted with theaminoalcohol in the presence of a gem-dialkoxyalkane, such as2,2-dimethoxypropane, and a strong organic acid or anhydrous Lewis acidcatalyst. In either case, a 2,2-dialkyl-1-glyoxylyloxazolidine VII isformed. Typical catalysts include pyridinium toluenesulfonate,toluenesulfonic acid, methanesulfonic acid, scandium triflate, borontrifluoride etherate and the like. In the enol ether, R^(5') representsthe remainder of residue R⁵ in which the first methylene is incorporatedinto the enol. The 2,2-dialkyl-1-glyoxylyloxazolidine is reacted asbefore with an excess of a Grignard reagent in an ethereal solvent at20° to -78° C. to provide a reaction mixture containing a2,2-dialkyl-1-(β-hydroxy-α-oxomethyl)oxazolidine VIII; a singlediastereomer of 2,2-dialkyl-1-(β-hydroxy-α-oxomethyl)oxazolidine isisolated from the reaction mixture; and the2,2-dialkyl-1-(β-hydroxy-α-oxomethyl)oxazolidine is hydrolyzed toprovide an α-hydroxycarboxylic acid or α-hydroxycarboxylate saltenriched in one enantiomer. As shown, the hydrolysis may be carried outin two steps: the first with aqueous mineral acid to cleave theoxazolidine (to give IX) and the second with alkali metal hydroxide in ahigh boiling solvent to cleave the amide (to give V). Alternatively, thesecond step may be accomplished enzymically. Suitable enzymes includelipases, such as Chiralzyme L-1™, Chiralzyme L-6™, 305™ (all availablefrom Boehringer-Mannheim), Chiroclec PC™, Pepticlec™ (available fromAltus Biologics) and AK™ (available from Amano); proteases such asMaxatase™ (available from Gist Brocades) and amide hydrolases, such aslysozyme (from Nagase). In preferred embodiments, the prochiralα-ketocarboxylic acid is phenylglyoxylic acid or cyclohexylglyoxylicacid and the vicinal aminoalcohol is 2-amino-1-cyclopentanol,1-amino-2-tetralinol or 1-amino-2-indanol. In most cases the optimalenol ether is 2-methoxypropene. A typical acid catalyst ismethansulfonic acid or toluenesulfonic acid, and the Grignard reagent isan arylmagnesium halide or cyclohexylmagnesium halide.

Although this invention is susceptible to embodiment in many differentforms, preferred embodiments of the invention are shown below. It shouldbe understood, however, that the present disclosure is to be consideredas an exemplification of the principles of this invention and is notintended to limit the invention to the embodiments illustrated.

Abbreviations and Definitions

The following is a dictionary of abbreviations and terms. All of them donot necessarily appear in the text:

    ______________________________________                                        Ac =    acetyl                                                                  Boc = t-butyloxy carbonyl                                                     Bu = butyl                                                                    c- = cyclo                                                                    DBU = diazabicyclo[5.4.0]undec-7-ene                                          DCM = dichloromethane = methylene chloride = CH.sub.2 Cl.sub.2                DCC = dicyclohexylcarbodiimide                                                DIC = diisopropylcarbodiimide                                                 DIEA = diisopropylethyl amine                                                 DMAP = 4-N,N-dimethylaminopyridine                                            DMF = N,N-dimethylformamide                                                   DMSO = dimethyl sulfoxide                                                     DVB = 1,4-divinylbenzene                                                      EEDQ = 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline                         EtOAc = ethyl acetate                                                         Fmoc = 9-fluorenylmethoxycarbonyl                                             GC = gas chromatography                                                       HATU = O-(7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium                   hexafluorophosphate                                                          HOAc = acetic acid                                                            HOBt = hydroxybenzotriazole                                                   Me = methyl                                                                   mesyl = methanesulfonyl                                                       NMO = N-methylmorpholine oxide                                                PEG = polyethylene glycol                                                     Ph = phenyl                                                                   PhOH = phenol                                                                 PfP = pentafluorophenol                                                       PyBroP = bromo-tris-pyrrolidino-phosphonium hexafluorophosphate                      rt = room temperature                                                  sat'd = saturated                                                             s- = secondary                                                                t- = tertiary                                                                 TBDMS = t-butyldimethylsilyl                                                  TFA = trifluoroacetic acid                                                    THF = tetrahydrofuran                                                         TMS = trimethylsilyl                                                          Ts or Tos = tosyl = p-toluenesulfonyl                                         Trt = triphenylmethyl                                                       ______________________________________                                    

EXPERIMENTAL DETAILS (Examples)

Aminoalcohol Chiral Auxiliary Preparation:

N-tosyl-cis-(1R,2S)-aminoindanol: To a suspension of cis-(1R,2S)-aminoindanol (14.9 g, 0.1 mol) in dichloromethane (400 mL) at 0° C.was added triethylamine (20 mL), followed by addition of TsCl (18.5 g,0.1 mol). The reaction mixture was stirred for 30 min at rt and washedwith water (2-100 mL), dried with sodium sulfate, and filtered. Thefiltrate was then concentrated to remove most of the solvent, followedby addition of hexane (150 mL). The solids formed were collected byfiltration and dried to give 26 g (yield 98%). Similarly,N-tosyl-cis-(1S,2R)-aminoindanol (its enantiomer) was prepared startingwith the (1S,2R)-isomer of aminoindanol. ¹ H NMR (CDCl₃) δ 2.05 (broads, 1H), 2.46 (s, 3H), 2.82-2.88 (d, J=16 Hz, 2.95-3.06 (dd, J1=Hz, J2=16Hz, 1H), 4.30 (m, 1H), 4.66 (m, 1H), 5.40 (m, 1H), 7.04-7.20 (m, 4H),7.32-7.36 (d, J=8 Hz, 2H), 7.84-7.90 (d, J=8 Hz, 2H). ¹³ C-NMR δ 21.51,39.14, 61.18, 72.76, 124.44, 125.23, 127.03, 127.14, 128.34, 129.75,137.47, 139.40, 143.64.

N-Tosyl-trans-(1R,2R)-aminoindanol: By using the same tosylationprocedure (yield 86%): ¹ H NMR (CDCl₃) δ 2.40 (s, 3H), 2.55 (m, 1H),2.80 (m, 1H), 3.20 (m, 1H), 3.8-4.6 (broad s, 1H), 4.44 (s, 2H), 6.90(d, J=4 Hz, 1H), 7.10-7.30 (m, 4H), 7.36-7.39 (d, J=6 Hz, 1H), 7.88-7.96(d, J=6 Hz, 2H).

N-Tosyl-trans (1R,2R)-cyclohexylaminoalcohol: ¹ H NMR (CDCl₃) δ1.00-1.20 (m, 4H), 1.5-1.8 (m, 3H), 2.00 (m, 1H), 2.44 (s, 3H), 2.7-2.95(m, 2H), 3.22-3.35 (m, 1H), 4.80 (broad s, 1H), 7.25-7.28 (d, J=7.5 Hz,2H), 7.77-7.80 (d, J=7.5 Hz, 2H).

N-Methyl-N-tosyl-(1R,2S)-aminoindanol (89% yield): 1H NMR (CDCl₃) δ 2.47(s, 3H), 2.69 (s, 3H), 2.87-2.94 (d,d, J1=5.1 Hz, J2=16.5 Hz, 1H),3.17-3.25 (d,d, J1=7.2 Hz, J2=16.8 Hz, 1H), 4.67-4.71 (m, 1H), 5.23-5.29(m, 1H), 6.39-6.42 (d, J=4.6 Hz, 1H), 7.05 (m, 1H), 7.22 (m, 2H),7.36-7.39 (d, J=8.1 Hz, 2H), 7.81-7.84 (d, J=8.1 Hz, 2H). ¹³ C (75 MHZ)δ 21.56, 32.38, 39.56, 64.22, 72.88, 125.31, 125.47, 126.96, 127.17,128.81, 129.86, 16.58, 136.70, 140.85, 143.64.

N,N-Dimethyl-cis-(1R,2S)-aminoindanol: Cis-(1R,2S)-aminoindanol (5 g)was dissolved in aqueous formaldehyde (18 mL) and formic acid (10 mL).The reaction mixture was heated to 70° C. for 40 h, and cooled to rt,suspended in ethyl acetate (60 mL) and added potassium carbonate tillbasic, the organic phase was separated and washed with brine, dried withsodium sulfate, and filtered to remove the drying agent. The filtratewas concentrated to give the oil, which was solidified on standing (4.5g, 76%). ¹ H NMR (CDCl₃) δ 2.25 (s, 6H), 2.80 (m, 1H), 3.24 (m, 1H),4.06 (d, J=6 Hz, 1H), 4.42 (m, 1H), 4.20-4.60 (broad s, 1H), 7.17-7.38(m, 4H). ¹³ C (75 MHZ) δ 41.24, 43.15, 69.54, 69.74, 125.51, 126.33,126.39, 128.50, 138.33, 141.62.

N-methyl-cis-(1R,2S)-aminoindanol: cis-(1R,2S)-aminoindanol (14.9 g) wassuspended in toluene (250 mL), followed by addition of formic acid (6mL). The reaction mixture was heated at reflux for 3 h, then distilledoff toluene (60 mL). The residue was then cooled to -10° C., theprecipitate was collected by filtration and dried to give 15 g formylamide intermediate. The intermediate (14 g) was suspended in THF (250mL) and BH₃.Me₂ S (10 M, 12 mL) was added in 5 min cooling withice-water bath. After the addition, the reaction mixture was heated atreflux for 4 h and stirred at 60° C. for 60 h. The solution was thencooled to 0° C., quenched with methanol (100 mL), and concentrated togive a white solid residue. The solid was suspended in methanol (100 mL)and concentrated again. The residue solid was then suspended in ethylacetate (200 mL) and followed by an usual aqueous workup to give 12.5 g(94% yield). ¹ H NMR (CDCl₃) δ 2.60 (s, 3H), 2.4-2.9 (broad s, 2H),2.93-3.10 (m, 2H), 3.94-3.96 (d, J=5.1 Hz, 1H), 4.40-4.47 (m, 1H), 7.23(m, 4H). ¹³ C (75 MHZ) δ 35.19, 39.62, 67.63, 70.25, 123.64, 125.65,126.63, 128.02, 141.11, 142.03.

Substrate Preparation:

N,N-Dimethyl-cis-(1R,2S)-1-aminoindanyl phenylglyoxylate (general method1 via DCC coupling): To a solution of phenylglyoxylic acid (1.1 g) indichloromethane (20 mL) was added DCC (1.65 g), DMAP (0.5 g) andN,N-Dimethyl-cis-(1R,2S)-1-aminoindanol (1.1 g). The reaction mixturewas stirred for 20 h at rt, filtered through Celite and concentrated togive an oil. The product was isolated by silica gel columnchromatography (EtOAc:Hex=3:7) to give a colorless oil. ¹ H NMR (CDCl₃)δ 2.30 (s, 6H), 3.20-3.40 (m, 2H), 4.58 (d, J=7 Hz, 1H), 5.72 (m, 1H),7.23-7.66 (m, 7H), 8.20 (d, J=7.5 Hz). ¹³ C (75 MHZ) δ 37.11, 41.79,67.66, 76.91, 124.95, 126.15, 126.94, 128.45, 128.71, 130.34, 132.52,134.77, 138.30, 139.02, 164.00, 186.89.

Cis-(1R,2S)-1-tosylaminoindanyl phenylglyoxylate (general method 2 viaphenylglyoxyl chloride): Phenylglyoxylic acid (41 g, 0.27 mol) was addedthionyl chloride (41 mL), and heated to 70-75° C. for 2 h. The reactionmixture was then concentrated to remove excess thionyl chloride. Theresidue was then dissolved in dichloromethane (100 mL), and added to asolution of N-tosyl-cis-(1R, 2S)-aminoindanol (60 g, 0.2 mol), andtriethylamine (30 mL) in dichloromethane (800 mL) at 0° C. over a periodof 5 min. The reaction mixture was stirred for 15 min. and washed withwater (300 mL), 10% acetic acid (2×100 mL), and water (300 mL), anddried with sodium sulfate. The drying agent was removed by filtration,the filtrate was concentrated to ca 50 mL, followed by addition of amixture of ethyl acetate and hexane (3:7, 400 mL). White precipitate wascollected by filtration, dried to give 58 g product (67%). ¹ H NMR δ2.39 (s, 3H), 3.05-3.11 (d, J=17.4 Hz, 1H), 3.19-3.27 (d,d, J1=17.4 Hz,J2=4.8 Hz), 1H), 5.08-5.14 (m, 1H), 5.30-5.33 (d, J=10.5 Hz, 1H),5.43-5.46 (m, 1H), 7.18-7.30 (m, 6H), 7.45-7.50 (m, 2H), 7.61-7.66 (m,1H), 7.83-7.86 (d, J=8.4 Hz, 2H), 7.92-7.95 (d, J=8.4 Hz, 2H). ¹³ C-NMRδ 21.39, 37.11, 59.62, 77.13, 124.04, 124.89, 126.88, 127.41, 128.64,128.76, 129.79, 129.95, 131.90, 134.91, 137.55, 137.99, 138.99, 143.66,162.26, 185.03.

Cis-(1R,2S)-1-N-tosyl-N-methyl-aminoindanyl phenylglyoxylate (method 2):except that the final product as thick oil by silica gel chromatographyusing ethyl acetate: hexane (3:7) as eluate (77%). ¹ H NMR 2.33 (s, 3H),2.69 (s, 3H), 3.08-3.15 (dd, J1=3 Hz, J2=17.4 Hz, 1H), 3.32-3.40 (dd,J1=6.6 Hz, J2=17.4 Hz), 5.76-5.78 (d, J=6.3 Hz, 1H), 5.86 (m, 1H),6.68-6.70 (d, J=7.5 Hz, 1H), 7.10-7.18 (m, 1H), 7.24-7.28 (m, 5H),7.48-7.54 (m, 2H), 7.63-7.68 (m, 1H), 7.77-7.80 (d, J=8.1 Hz), 8.01-8.04(d, J=8.1 Hz, 2H). ¹³ C-NMR δ, 21.37, 32.20, 37.54, 62.86, 76.91,124.81, 125.28, 127.08, 127.43, 128.83, 129.74, 130.18, 132.14, 134.91,136.56, 138.87, 143.45, 162.18, 184.86.

Trans-(1R,2R)-2-Tosylaminocyclohexyl phenylglyoxylate (method 2): It wasisolated by flash chromatography (EtOAc:Hexane=3:7) in 75% yield. ¹HNMR, δ 1.23-1.38 (m, 3H), 1.42-1.56 (m, 1H), 1.58-1.68 (m, 1H),1.70-1.78 (m, 1H), 1.94-2.02 (m, 1H), 2.08-2.20 (m 1H), 2.29 (s, 3H),3.30-3.42 (m, 1H), 4.80-4.92 (m, 1H), 5.00-5.03 (d, J=8.4 Hz, 1H),7.08-7.11 (2H, d, J=8.7 Hz, 2H), 7.49-7.54 (m, 2H), 7.64-7.70 (m, 3H),8.00-8.03 (m, 2H). ¹³ C-NMR δ, 21.40, 23.41, 23.90, 30.65, 32.84, 56.12,76.35, 126.80, 128.85, 129.60, 130.22, 132.23, 134.86, 137.91, 143.24,163.48, 185.57.

Cis-1,2,3,4-tetrahydro-1-Tosylamino-naphthyl phenylglyoxylate (method2): ¹ H NMR, δ 1.93-2.10 (m, 1H), 2.37-2.40 (m, 1H), 2.39 (s, 3H),2.70-2.80 (m, 1H), 2.86-3.00 (m 1H). 4.84 (m 1H), 5.04 (m, 1H), 5.30 (m,1H), 7.05-7.30 (m, 6H), 7.46-7.54 (m, 2H), 7.62-7.68 (m, 1H), 7.78-7.83(m 2H), 7.93-7.98 (M, 2H). ¹³ C-NMR δ, 21.51, 24.30, 24.87, 53.68,72.91, 126.77, 126.88, 127.93, 128.16, 128.71, 128.93, 129.86, 130.03,132.15, 132.93, 135.01, 135.72, 138.05, 143.68, 163.09, 185.47.

Cyclohexylglyoxylate Preparation:

Synthesis of Ethyl cyclohexyloxoacetate: Cyclohexyl magnesium bromide(Aldrich) in ether (2 M, 150 mL) was pumped under vacuum to remove ethylether, at rt, the residue obtained was then dissolved in anhydrous THF(100 mL) while cooled with an ice water bath. The solution was thenadded to a solution of diethyl oxalate (60 g ) in THF (150 mL) at-30--40° C. in 10 min. The reaction mixture was warmed to 0° C. for 5min, and quenched with 10% HCl (100 mL), extracted with ethyl acetate(200 mL), the extract was washed with water (30 mL), brine (50 mL) anddried with sodium sulfate, then filtered. The filtrate was concentratedto give an oil. It was distilled 40-50° C. at 1 mm Hg to remove thestarting material and the left over is the product (total of 46 g, 86%yield, purity >90%, it can be distilled at 1 mm Hg, 75-80° C.). ¹ H NMRδ: 1.20-1.40 (m, 8H), 1.62-1.94 (m, 5H), 3.02 (broad s, 1H), 4.30 (q,J=8 Hz, 2H). ¹³ C-NMR δ 13.91, 25.11, 25.58, 27.36, 46.13, 62.07,161.84, 197.51.

Synthesis of cyclohexylglyoxylic acid: To a solution of ethylcyclohexyloxoacetate (46 g) in MeOH (25 mL) was added water (60 mL) andNaOH (50% 20 mL) at 0-15° C. The reaction mixture was heated to 60° C.for 1.5 h. The reaction mixture was cooled with ice-water bath, andacidified with 15% HCl till pH 1. The mixture was extracted with ethylacetate (2×250 mL). The extracts were washed with brine, dried withsodium sulfate. The drying agent was removed by filtration and thesolvent was removed to give a low melting solid (39 g, 99%). ¹ H NMR: δ1.15-1.40 (m, 5H,), 1.62-1.96 (m, 5H). 3.20 (m, 1H), 9.4 (s, 1H). ¹³C-NMR δ, 25.93, 25.76, 27.89, 45.04, 160.90, 198.29.

Synthesis of cis-(1S,2R)-1-tosylaminoindanyl cyclohexyloxylate: To asolution of cyclohexyloxylic acid (4.7 g) in dichloromethane (30 mL) at0° C. was added oxalyl chloride (4.0 mL), followed by addition of 1 dropof DMF. The reaction mixture was stirred at 0° C. for 3 h, followed bythe removal of solvent. The residue was then dissolved indichloromethane (30 mL) to give total volume of 34 mL. Total of 22 mL ofthe solution was then added to a solution of cis-(1S,2R)-N-tosylaminoindanol (4.5 g, 15 mmol) and triethyl amine (3.2 mL) indichloromethane (50 mL) at 0° C. The reaction mixture was thenconcentrated to remove dichloromethane, the resulting residue was thendissolved in ethyl acetate (50 mL), washed the solution with water (30mL), and 1% HCl (20 mL), water (20 mL), and dried with sodium sulfate.The drying agent was removed by filtration and the filtrate wasconcentrated to give a foaming solid the product was isolated by flashchromatography using ethyl acetate and hexane (3:7) to give 4.7 g solidin 72% yield. ¹ H NMR. δ 1.15-1.36 (m, 5H), 1.56-1.80 (m, 5H), 2.46 (s,3H), 2.82 (m, 1H). ¹³ C NMR δ 21.44, 25.07, 25.48, 27.31, 37.03, 46.09,59.60, 76.42, 124.14, 124.85, 126.89, 127.46, 128.69, 129.70, 137.67,137.93, 138.99, 143.64, 160.48, 196.27. M+(440)

Grignard Addition to the Substrate:

Phenyl Grignard addition to cis-(1S,2R)-1-tosylaminoindanylcyclohexyloxylate: To a solution of phenyl Grignard (3 M 23 mL) in THF(60 mL) was added cis-(1S,2R)-1-tosylaminoindanyl cyclohexyloxylate (10g, 22 mmol) in THF (60 mL) at 0° C. over a period of 5 min. The reactionmixture was then stirred for 15 min, followed by addition of 10% HCl (20mL). The reaction mixture was then added water (20 mL), extracted withethyl acetate (60 mL). The extract was washed with water (30 mL), brine(40 mL), and concentrated to give an oil, which was purified bycrystallization with ethyl acetate and hexane to give to give theproduct (9.2 g, 77% yield). ¹ H NMR δ 0.92-1.16 (m 4H), 1.28-1.28-1.43(m, 2H), 1.44-1.54 (m, 1H), 1.54-1.68 (m, 2H), 1.78-1.88 (m, 1H),1.95-2.04 (m, 1H), 2.43 (s, 3H), 2.53-2.58 (d, J=17.4 Hz, 1H), 2.93-2.30(d, d, J1=4.5 Hz, J2=17.4 Hz), 3.51 (s, 1H), 4.99-5.04 (m, 1H),5.12-5.16 (d, J=10.5 Hz, 1H), 5.23-5.56 (m, 1H), 6.96-7.20 (m, 4H),7.21-7.38 (m, 7H), 7.76-7.79 (d, J=8.4 Hz, 2H). ¹³ C-NMR δ 21.56, 25.30,26.06, 26.31, 27.55, 36.87, 45.87, 59.62, 78.00, 81.32, 123.97, 125.01,125.54, 126.93, 127.32, 127.51, 127.94, 128.66, 129.88, 137.49, 138.31,140.03, 143.89, 174.56. Mass. M+519.

Cyclohexyl Grignard addition to cis-(1R,2S)-1-tosylaminoindanylphenylgloxylate (ZnCl₂ catalyzed): Cyclohexyl magnesium chloride (2 M,50 mL, 0.1 mol) was added to a solution of ZnCl₂ (1 M, 80 mL, 0.08 mol)in ethyl ether at 0° C. over a period of 3 min. The reaction mixture wascooled to -78° C., followed by addition ofcis-(1R,2S)-1-tosylaminoindanyl phenylglyoxylate (8.6 g, 0.02 mol) inTHF (50 mL). The reaction mixture was then warmed to rt, stirred for 1h, and quenched with ammonium chloride solution (40 mL), followed byaddition of ethyl acetate (100 mL), water (150 mL) and 10% HCl (40 mL).The organic phase was separated, aqueous phase was extracted with ethylacetate (150 mL), the organic phases were combined and washed with water(100 mL), brine (30 mL), and dried over sodium sulfate. The drying agentwas removed by filtration, and the filtrate was concentrated to give 9 gcrude product with de of (85:15). The crude product was crystallizedethyl acetate and hexane (2:3, 100 mL) to give 5.6 g (55%)diastereomerically pure product. ¹ H NMR δ 0.80-1.10 (m, 4H), 1.12-1.40(m, 3H), 1.50-1.63 (m, 2H), 1.62-1.73 (m, 1H), 1.85-1.95 (m, 1H), 2.40(s, 3H), 2.85-3.10 (m, 2H), 3.64 (s, 1H), 4.48-4.52 (d, J=10.5 Hz, 1H),4.80 (m, 1H), 4.87-4.92 (m, 1H), 7.02-7.12 (m, 4H), 7.18-7.52 (m, 9H).13C-NMR d≡21.50, 25.26, 25.94, 26.82, 37.00, 44.48, 59.99, 77.31, 80.46,124.22, 124.67, 125.84, 126.53, 127.58, 128.23, 128.63, 128.82, 129.64,137.24, 137.72, 139.36, 140.44, 143.55, 174.40.

Chiral CHPGA Preparation (Base Hydrolysis)

General Procedure for the hydrolysis of CHPGA esters: To suspension ofcis-(1S,2R)-1-tosylaminoindanyl (S)-cyclohexylmandalate (1.04 g) inwater (10 mL) and methanol(10 mL) was added 50% sodium hydroxide (0.8mL). The reaction mixture was heated to 70-80° C. for 2 h, cooled to rt,and added HCl (6N) till neutral pH, followed by addition of potassiumcarbonate (10 mL) till pH 10-11. The precipitate was formed and wascollected by filtration to give the crude ligand (0.8 g). The filtratewas extracted with ethyl acetate (5 mL). the aqueous phase was thenacidified with 6N HCl till pH 1, then extracted with ethyl acetate (40mL). The extract was washed with brine and concentrated to give 350 mgproduct with 98% ee. ¹ H NMR δ 1.00-1.50 (m 6H), 1.66 (m, 3H), 1.8 (m,1H), 2.24 (m, 1H), 3.40 (broad s, 1H), 7.20-7.40 (m, 3H), 7.60-7.65 (d,J=2H), 10.0 (broad s, 1H). ¹³ C-NMR δ 25.40, 26.10, 26.24, 27.36, 45.67,80.99, 125.92, 127.70, 128.18, 139.82, 180.80. M+(234).

Oxazolidine Route (Scheme 5)

Preparation of oxazolidine VII (R⁴ =R⁵ =methyl; R⁶ =phenyl; A=indane): Asolution of(1S,2R)-1-aminoindanol-2-ol (14.9 g, 100.0 mmol) in 220 ml ofdry THF and triethylamine (14.57 ml, 104.8 mmol) in a 500 mL roundbottom flask equipped with a thermocouple probe, mechanical stirrer, anda nitrogen inlet adapter and bubbler, was cooled to 0° C. Thenbenzoylformoyl chloride I' (16.8 g, 100.0 mmol) was added over 15 min.After addition, the mixture was allowed to warm to rt and stirred for anadditional 30 min. The reaction was treated with pyridiniump-toluenesulfonate (4.0 g, 16.0 mmol) and stirred for 10 minutes. Then,2-methoxypropene (21.0 mL, 223 mmol) was added and reaction was heatedto 40° C. for 5 h. The reaction mixture was cooled to 20° C., andpartitioned with ethyl acetate (150 mL) and 5% aqueous NaHCO₃ (125 mL).The mixture was agitated and the layers were separated. The ethylacetate extract was concentrated in vacuo. Cyclohexane (150 mL) wasadded to the oil and the mixture was concentrated again in vacuo toprovide crude product. The oil was chromatographed using 15%ethylacetate/hexane as eluent to provide 25.5 g (80%) of VII as an oil.¹ H NMR (CDCl₃, 300 MHZ) δ 8.10 (d, J=7 Hz, 1H), 7.68-7.10 (m, 8H), 5.35(d, J=4 Hz, 1H), 4.89 (t, J=4 Hz, 1H), 3.08 (m, 2H), 1.83 (s, 3H), 1.49(s, 3H). ¹³ C NMR (CDCl₃, 75 MHZ) 19.6, 22.1, 31.7, 61.1, 92.6, 121.0,122.5, 122.8, 124.1, 125.3, 125.4, 130.1, 130.4, 135.5, 136.1, 158.9,160.2.

Addition of Grignard to Prepare Oxazolidine VIII (R⁷ =cyclohexyl): Asolution of VII in dry THF (400 mL) was cooled to -78° C. and treatedwith cyclohexyl magnesium chloride (122.5 mL, 245 mmol, 2M solution inether). The reaction was allowed to stir at -78° C. for 1 h and slowlywarmed to rt and allowed to stir an additional 2 h. The reaction mixturewas partitioned with water (400 mL) and ethyl acetate (400 mL). Thelayers were separated . The ethyl acetate layer was concentrated invacuo and chromatographed using 10% ethylacetate/hexane as eluent toprovide 14.7 g (52%) of VIII as a solid. ¹ H NMR (CDCl₃, 300 MHZ) δ7.61-7.21 (m, 9H), 5.68 (d, J=3 Hz, 1H), 4.32 (m, 1H), 3.00 (s, 2H),2.68 (m, 1H), 2.21 (m, 1H), 1.97-1.09 (m, 10 H), 1.49 (s, 3H), 1.30 (s,3H). ¹³ C NMR (CDCl₃, 75 MHZ) 9.8, 19.0, 21.8, 22.0, 22.5, 24.0, 31.7,41.8, 56.0, 61.9, 75.0, 79.5, 93.6, 120.7, 120.9, 122.0, 122.2, 122.6,123.7, 123.8, 136.2, 137.6, 138.0, 164.1.

Preparation of amide IX: Oxazolidine VIII (8.9 g, 21.9 mmol) wasdissolved in 30 mL of THF and 30 mL of 6N HCl at rt. After stirring atrt for 2 h, the reaction was neutralized with 3N KOH solution and thevolatiles were removed in vacuo. The reaction was partitioned with ethylacetate (50 mL) and water (50 mL) and the ethyl acetate layer wasconcentrated in vacuo to provide 7.8 g of the amide (97%). ¹ H NMR(CDCl₃, 300 MHZ) δ 7.44-6.88 (m, 9H), 5.29 (d, J=9 Hz, 1H), 4.51 (m,1H), 3.12 (d, J=15 Hz, 1H), 2.92 (d, J=15 Hz, 1H), 2.48 (m, 1H),1.91-0.97 (m, 10H). 13C NMR (CDCl₃, 75 MHz) 21.2, 21.8, 22.5, 35.2,40.1, 52.7, 69.3, 77.6, 119.7, 120.7, 120.8, 120.9, 122.4, 123.7, 124.0,135.4, 136.1, 137.2, 170.2.

Preparation of CHPGA (V): Adduct IX (287 mg, 0.76 mmol) was dissolved in10 mL of ethylene glycol under argon and allowed to reflux for 24 h. Thereaction was allowed to cool. It was partitioned between 100 mL of waterand 100 mL of ethyl acetate. The ethyl acetate layer was concentrated invacuo and chromatographed using 2% MeOH/EtOAc as eluent to providechiral CHPGA in 52% yield.

What is claimed is:
 1. A process for the enantioselective synthesis of achiral α-hydroxycarboxylate comprising:(a) reacting a prochiralα-ketocarboxylic acid with a single enantiomer of an N-substitutedvicinal aminoalcohol of cyclopentane, cyclohexane, cycloheptane, indane,tetralin or benzosuberane to form an ester of said α-ketocarboxylicacid; (b) reacting said ester of said α-ketocarboxylic acid with anexcess of a Grignard reagent in an ethereal solvent at 20° to -78° C. toprovide a reaction mixture containing a diastereomer of anα-hydroxycarboxylate ester; and (c) separating a single diastereomer ofsaid α-hydroxycarboxylate ester from said reaction mixture.
 2. A processaccording to claim 1 comprising the additional step of:(d) hydrolyzingsaid α-hydroxycarboxylate ester to provide an α-hydroxycarboxylic acidor α-hydroxycarboxylate salt enriched in one enantiomer.
 3. A processaccording to claim 1 wherein said step of separating a singlediastereomer of α-hydroxycarboxylate ester from the reaction mixture isaccomplished by fractional crystallization or chromatography.
 4. Aprocess according to claim 1 or 2 wherein said reacting a prochiralα-ketocarboxylic acid with a single enantiomer of a vicinal aminoalcoholis carried out by forming an acid chloride of said acid and reactingsaid acid chloride with said aminoalcohol.
 5. A process according toclaim 1 or 2 wherein said reacting a prochiral α-ketocarboxylic acidwith a single enantiomer of a vicinal aminoalcohol is carried out bybringing together in solution a carbodiimide, said acid and saidaminoalcohol.
 6. A process according to claim 1 wherein said prochiralα-ketocarboxylic acid is phenylglyoxylic acid, said single enantiomer ofa vicinal aminoalcohol is a single enantiomer of a vicinal aminoalcoholchosen from 2-tosylamino-1-cyclopentanol, 2-tosylamino-1-cyclohexanol,1-tosylamino-2-indanol, 1-tosylamino-2-tetralinol and1-dimethylamino-2-indanol.
 7. A process according to claim 1 whereinsaid prochiral α-ketocarboxylic acid is cyclohexylglyoxylic acid, saidsingle enantiomer of a vicinal aminoalcohol is a single enantiomer of avicinal aminoalcohol chosen from 2-tosylamino-1-cyclopentanol,2-tosylamino-1-cyclohexanol, 1-tosylamino-2-indanol,2-tosylamino-2-phenyl-1-cyclohexanol and 1-dimethylamino-2-indanol.
 8. Aprocess for producing an optically pure isomer of anα-cyclohexylphenylglycolate according to claim 1 comprising the stepsof:(a) reacting phenylglyoxylic acid with a single enantiomer of avicinal aminoalcohol of cyclopentane, cyclohexane, cycloheptane, indane,tetralin or benzosuberane to form an ester of said phenylglyoxylic acid;(b) reacting said ester of phenylglyoxylic acid with an excess ofcyclohexylmagnesium halide in an ethereal solvent at 20° to -78° C. toprovide a reaction mixture containing an α-cyclohexylphenylglycolateester; and (c) separating a single diastereomer ofα-cyclohexylphenylglycolate ester from said reaction mixture.
 9. Aprocess for producing an optically pure isomer of anα-cyclohexylphenylglycolate according to claim 1 comprising the stepsof:(a) reacting cyclohexylglyoxylic acid with a single enantiomer of avicinal aminoalcohol of cyclopentane, cyclohexane, cycloheptane, indane,tetralin or benzosuberane to form an ester of said cyclohexylglyoxylicacid; (b) reacting said ester of cyclohexylglyoxylic acid with an excessof phenylmagnesium halide in an ethereal solvent at 20° to -78° C. toprovide a reaction mixture containing an α-cyclohexylphenylglycolateester; and (c) separating a single diastereomer ofα-cyclohexylphenylglycolate ester from said reaction mixture.
 10. Aprocess according to either of claims 8 or 9 additionally comprising thestep of:(d) hydrolyzing said single diastereomer ofα-cyclohexylphenylglycolate ester to provide α-cyclohexylphenylglycolicacid or an α-cyclohexylphenylglycolate salt enriched in one enantiomer.11. A process for the enantioselective synthesis of a chiralα-hydroxycarboxylate comprising:(a) reacting an acid chloride of aprochiral α-ketocarboxylic acid with a single enantiomer of a vicinalamino alcohol of cyclopentane, cyclohexane, cycloheptane, indane,tetralin or benzosuberane in the presence of an enol ether of a loweralkylketone or a dialkoxy lower alkane and an acid catalyst to form a2,2-dialkyl-1-glyoxylyloxazolidine; (b) reacting said2,2-dialkyl-1-glyoxylyloxazolidine with an excess of a Grignard reagentin an ethereal solvent at 20° to -78° C. to provide a reaction mixturecontaining a 2,2-dialkyl-1-(β-hydroxy-α-oxomethyl)oxazolidine (c)separating a single diastereomer of2,2-dialkyl-1-(β-hydroxy-α-oxomethyl)oxazolidine from said reactionmixture; and (d) hydrolyzing said2,2-dialkyl-1-(β-hydroxy-α-oxomethyl)oxazolidine to provide anα-hydroxycarboxylic acid or α-hydroxycarboxylate salt enriched in oneenantiomer.
 12. A process according to any of claims 1, 8, 9 or 11wherein a salt of zinc, cerium, titanium, iron or copper is added tostep (b).
 13. A process according to claim 11 wherein said hydrolysis iscarried out sequentially with aqueous mineral acid and then alkali metalhydroxide in a high boiling solvent.
 14. A process according to claim 11wherein said hydrolysis is carried out sequentially with aqueous mineralacid and then with an enzyme.
 15. A process according to claim 14wherein said enzyme is chosen from lipases, proteases and amidehydrolases.
 16. A process according to claim 11 wherein said prochiralα-ketocarboxylic acid is phenylglyoxylic acid, said single enantiomer ofa vicinal aminoalcohol is a single enantiomer of a vicinal aminoalcoholchosen from 2-amino-1-cyclopentanol, 2-amino-1-cyclohexanol and1-amino-2-indanol, said enol ether of a lower alkylketone is2-methoxypropene, said acid catalyst is chosen from pyridiniumtoluenesulfonate, toluenesulfonic acid and methansulfonic acid, and saidGrignard reagent is a cycloalkylmagnesium halide.
 17. A processaccording to claim 11 wherein said prochiral α-ketocarboxylic acid iscyclohexylglyoxylic acid, said single enantiomer of a vicinalaminoalcohol is a single enantiomer of a vicinal aminoalcohol chosenfrom 2-amino-1-cyclopentanol, 2-amino-1-cyclohexanol and1-amino-2-indanol, said enol ether of a lower alkylketone is2-methoxypropene, said acid catalyst is chosen from pyridiniumtoluenesulfonate, toluenesulfonic acid and methansulfonic acid, and saidGrignard reagent is an arylmagnesium halide.
 18. A compound of formula##STR15## R³ is one or more substituents chosen independently from thegroup consisting of hydrogen, alkyl, alkoxyl and halo;R⁴ and R⁵ areindependently lower alkyl; n is 1, 2 or 3; and A is a cyclic residuechosen from the group consisting of cyclopentane, cyclohexane,cycloheptane, indane, tetralin or benzosuberane.
 19. A compound offormula ##STR16## wherein R³ is one or more substituents chosenindependently from the group consisting of hydrogen, alkyl, alkoxyl andhalo;R⁴ and R⁵ are independently lower alkyl; n is 1, 2 or 3; and A is acyclic residue chosen from the group consisting of cyclopentane,cyclohexane, cycloheptane, indane, tetralin or benzosuberane having aconfiguration such as to give rise to a single enantiomer or a mixtureof enantiomers enriched in one enantiomer.
 20. A compound according toclaim 18 or 19 wherein R³ is hydrogen.
 21. A compound according to claim18 or 19 wherein A is cyclopentane, cyclohexane, indane or tetralin. 22.A compound according to claim 18 or 19 wherein R⁴ and R⁵ are bothmethyl.